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BIOSIMILARS:
ALTERNATIVE REGULATORY PATHWAYS
American Conference Institute
FOLLOW-ON BIOLOGICS
June 22, 2010
Charles J. Raubicheck
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Frommer Lawrence & Haug LLP
BIOSIMILARS UNDER HATCH-WAXMAN
Section 505(b)(2) Regulatory Approval Pathway
• Section 505(b)(2)
• Added by Hatch-Waxman
• Clinical Studies Not Conducted By or For the NDA
Applicant
and
• No Right of Reference
• 505(b)(2) Applicant Can Rely on Clinical Data it
Does Not Develop (Innovator’s S/E Data)
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HATCH-WAXMAN: 505(b)(2) NDA (cont’d)
• Types of data for Reliance
• Published Literature (previous “Paper NDA”)
• FDA Finding of Safety and Effectiveness for a Drug
Approved Under a Full NDA
• 505(b)(2) Applicant Relies in Part on
Innovator’s S/E Data (505(b)(1)), Plus Data
the Applicant Itself Generates
• FDA’s Rationale: Preclude Unnecessary Clinical
Studies for What is Already Known About a
Drug
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HATCH-WAXMAN: 505(b)(2) NDA (cont’d)
• Announcements of 505(b)(2) Approach
• 1987 Parkman Letter (Modifications When
Clinical Data Required)
• Preambles: 1989 and 1992 ANDA Regulations
• 1999 Section 505(b)(2) Guidance
• Guidance – (b)(2) Applies to Changes to
Drugs Previously Approved Under a FULL
NDA
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HATCH-WAXMAN: 505(b)(2) NDA (cont’d)
• Bridging Studies:
• Usually Several Clinical Trials
• At Least One Phase II or Phase III
• Conference with FDA re Protocol
• Rare: Bioequivalence
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HATCH-WAXMAN: 505(b)(2) NDA (cont’d)
• Examples of Types of Changes
• Active Ingredient
• Dosage Form
• Strength
• Route of Administration
• Dosing Regimen
• Combination Product
• Indication
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HATCH-WAXMAN: 505(b)(2) NDA (cont’d)
Also, (key here):
• Naturally Derived or Recombinant Active
Ingredient
• Change to prior approved Active Ingredient
that is Chemically Synthesized or Derived
from Another Source
• Clinical Bridging Studies: Required to Show
that Active Ingredient Is the Same As the
Active Ingredient in a Drug Covered by an
Approved Full NDA
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SECTION 505(b)(2) NDA: CHALLENGES
REJECTED BY FDA
• Proprietary Data (Clinical and CMC)
• FDA Only Refers Internally
• Data Protected: No Public Disclosure
• Statute Doesn’t Preclude Reliance on Innovator’s
S/E Data
• No Unconstitutional Taking
• No Expectation of Confidentiality (Highly Regulated
Field)
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SECTION 505(b)(2) NDA: BIOSIMILARS
• No Statutory Exclusion
• Biologic Is a “Drug”
• Highly Similar Active Ingredient
• Precedent: Insulin (Historical)
• Need for Biosimilar Pathway
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SECTION 505(b)(2) NDA: BIOSIMILARS (cont’d)
Recent 505(b)(2) Approvals
• 2005 – HYLENEX (Recombinant
Hyaluronidase): Increases Absorption and
Dispersion of Other Injected Drugs
• Reliance: Amphastar® (bovine-derived)
• 2005 – FORTICAL (Recombinant Salmon
Calcitonin): Ostoporosis
• Reliance: Miacalcin® (Synthetic)
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SECTION 505(b)(2) NDA: BIOSIMILARS (cont’d)
• 2006 – OMNITROPE (Recombinant Somatropin):
Human Growth Hormone (rhGH)
• Reliance: Genotropin®
CASE STUDY: OMNITROPE
• Citizen Petitions (Pfizer, BIO, Genentech) Denied
• FDA Rationale
• 505(b)(2): Chemical Structure of Active Ingredient
“Highly Similar” (as in Biosimilars Act) (“Sameness” Not
Required)
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SECTION 505(b)(2) NDA: BIOSIMILARS (cont’d)
• rhGH a Relatively Simple Recombinant Protein
(Characterization, Purification)
• Highly Similar Characteristics: Pharmacokinetic,
Pharmacodynamic, Bioavailability
• Clinical Experience and Published Literature on rhGH
• Bridging Studies
• PK/PD Studies
• Phase III Clinical Trials (4)
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ANDA APPROVAL VEHICLE
• ANDA Must Be Filed for:
• Same Active Ingredient, Dosage Form, Strength,
Route of Administration, Indications
• Drug Product which Differs From Innovative Product
in One of the Above Respects, but
• Has an Approved Suitability Petition Allowing the
Change
• Does Not Require S/E Clinical Studies
• Can’t Be a 505(b)(2)
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ANDA APPROVAL VEHICLE (cont’d)
Example
• Ferring’s REPRONEX (Menotropins) for Infertility
• Active Ingredient: Follicle-Stimulating Hormone
(“FSH”)
• Citizen Petition Opposition: Serono’s Pergonal®
• FSH in REPRONEX Different From FSH in Pergonal®
(Different Isoforms of Hormone)
• ANDA Route Improper
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ANDA APPROVAL VEHICLE (cont’d)
• FDA Denied Citizen Petition: Natural Variation in
Carbohydrate Elements (Leading to Different
Isoforms of Hormone) “Not Clinically Significant”
(Similar to “No Clinically Meaningful Difference”
in New Biosimilar Definition)
• “Sameness” Standard Satisfied when Same
Primary Chemical Structure, Amino Acid
Sequence, Potency, and Degree of Batch to Batch
Uniformity
• Unusual for a Biologic
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ANDA APPROVAL VEHICLE (cont’d)
• D.C. Circuit (upholding FDA):
• “Same Active Ingredient”: Chemical Identity
to Extent Possible (Not Complete Identity)
• Isoform Variations Permissible under FDA’s “No
Clinical Significance” Criterion
• Reasonable Interpretation under Chevron:
Deference to FDA
• ANDA Vehicle Unlikely Now, due to
Biosimilars Act
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TRANSITIONAL PROVISIONS
• 505(b)(2) NDAs Permitted: For Biologics in
Same Product Class as Biologics Previously
Approved under (b)(2)
• Submitted Before Enactment Date (March 23,
2010), or Within 10 Years Thereafter
• All Biologics After Enactment Date: BLA or
ABLA
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TRANSITIONAL PROVISIONS (cont’d)
• All 505(b)(2) Approved Products: Deemed
to Have Approved BLAs 10 Years after
Enactment Date (Follow-On Products Then
Need ABLA)
• Until then, 505(b)(2) Procedures Apply
(including Patent Certification)
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BIOSIMILAR VIA FULL BLA
• Full BLA Alternative Pathway
• NEUTROVAL (Filgrastim; Similar to Neupogen®)
• Treatment of Neutropenia (Increases White
Blood Cells to Prevent Infection in Patients
Undergoing Chemotherapy)
• Accepted by FDA (February 2010): preBiosimilars Act
• Supported by 5 Clinical Studies
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